We propose to develop a new bioreactor system that would radically advance biomedical and clinical studies of human cells and engineered tissues. The project would address a long standing need for culture systems that provide high biologic fidelity along with the precise environmental control, real time imaging, and adaptive operating strategies, in configurations that are easy to use by a wide range of investigators. The use of currently available bioreactor systems has significantly advanced our ability to conduct fundamental and translational research. However, major limitations remain. There is a need for bioreactors that would combine several critical requirements: (i) provision of precisely controlled 3D environments resembling those encountered in vivo, (ii) application of multiple regulatory factors (molecular, physical, cell- and matrix- derived), (iii) modular designs for high-throughput and combinatorial studies, and (iv) live imaging compatibility for real-time insight. Our laboratory has been developing bioreactors for tissue engineering for almost two decades. We propose to integrate and advance our accumulated experience and resources to develop a truly advanced new bioreactor with broad relevance to biomedical and clinical research. Three specific aims will be pursued in an integrated fashion towards the optimization and full validation of the proposed bioreactor system. Aim 1 is to develop a bench-top bioreactor platform with culture modules consisting of self-sustained cartridges with medium flow and environmental control. Aim 2 is to develop bioreactor configurations with medium perfusion and mechanical loading, suitable for studies of habitually loaded cells and tissues. Aim 3 is to develop bioreactor configuration with perfusion, electrical and mechanical stretch, suitable for studies of electromechanically active cells and tissues. The proposed system will be based on a common platform providing a set of basic functions that will be interfaced with on-line imaging, environmental control, and data acquisition. The focus of our work will be on the biological requirements of stem cell and tissue engineering research, and the implementation of radically new engineering solutions for a bioreactor design. PUBLIC HEALTH RELEVANCE (provided by applicant): Development of bioreactors that would enable studies of human cells and engineered tissues under conditions similar to those in the body, with precise environmental control and live imaging would truly advance biological and medical research. We propose to develop such a bioreactor, with robust modular configuration that is easy to use and suitable for a very broad range of biomedical studies.